Our Alcohol Center focuses on the mechanisms by which alcohol abuse renders the lung and other organs susceptible to failure in response to stresses such as sepsis or trauma. Our epidemiological data suggest that as many as 75,000 patients with a history of alcohol abuse each year develop acute respiratory failure and related multiple organ failure, leading to substantial morbidity and mortality in these vulnerable patients. A hallmark of acute lung injury is disruption of the alveolar epithelial barrier that allows these critical gas-exchanging airways to flood with fluid and protein, ultimately leading to respiratory failure requiring mechanical ventilatory support. Tragically, despite aggressive medical and surgical care, these patients have a mortality of about 50% and frequently succumb to multiple organ failure. Therefore, it is critically important that we identify the mechanisms by which alcohol abuse renders the airways susceptible to injury. In Project 1 of our Center Grant proposal, we will focus on the potential role of transforming growth factor beta in ethanol-mediated alveolar epithelial barrier dysfunction. Transforming growth factor beta (TGFbeta) is a pluripotent cytokine that has recently been identified as a mediator of acute lung injury in animal models. However, its role in human lung disease, and alcohol-mediated lung injury in particular, is unknown. Preliminary data from our laboratory indicate that chronic ethanol ingestion in rats increases the expression of TGFbeta1 in the alveolar epithelial type II cells and macrophages, and potentiates the release of activated TGFbeta1 into the alveolar airspace during endotoxemia. Further, the alveolar epithelial cells from ethanol-fed rats appear to be primed for TGFbeta1 mediated barrier disruption as reflected by increased expression of TGFbeta1 receptors on their surface. Finally, we determined that alcoholic patients with acute lung injury have almost twice the levels of TGFbeta1 in their lung lavage fluid as non-alcoholic patients with lung injury. Therefore, we propose to examine ethanol-mediated expression and activation of TGFbeta1, and the relative importance of TGFbeta1 -mediated alveolar barrier disruption in the alcoholic lung. We will use isolated alveolar epithelial cells and macrophages, as well as intact lungs perfused ex vivo, from rats fed the Lieber-DeCarli diet for a minimum of 6 weeks. We have extensive experience with this model and these techniques, and have used them to make significant progress in identifying mechanisms by which alcohol abuse renders the lung susceptible to injury. In collaboration with other investigators in our Center, we will be able to examine in depth the novel hypothesis that ethanol-mediated aberrant expression and activation of TGFbeta1 causes alveolar barrier disruotion and contributes to the markedly increased risk of acute lung injury in alcoholic patients.